%0 Journal Article
%A Schedel, Anne
%A Friedrich, Ulrike Anne
%A Morcos, Mina N F
%A Wagener, Rabea
%A Mehtonen, Juha
%A Watrin, Titus
%A Saitta, Claudia
%A Brozou, Triantafyllia
%A Michler, Pia
%A Walter, Carolin
%A Försti, Asta
%A Baksi, Arka
%A Menzel, Maria
%A Horak, Peter
%A Paramasivam, Nagarajan
%A Fazio, Grazia
%A Autry, Robert
%A Fröhling, Stefan
%A Suttorp, Meinolf
%A Gertzen, Christoph
%A Gohlke, Holger
%A Bhatia, Sanil
%A Wadt, Karin
%A Schmiegelow, Kjeld
%A Dugas, Martin
%A Richter, Daniela
%A Glimm, Hanno
%A Heinäniemi, Merja
%A Jessberger, Rolf
%A Cazzaniga, Gianni
%A Borkhardt, Arndt
%A Hauer, Julia
%A Auer, Franziska
%T Recurrent Germline Variant in RAD21 Predisposes Children to Lymphoblastic Leukemia or Lymphoma.
%J International journal of molecular sciences
%V 23
%N 9
%@ 1422-0067
%C Basel
%I Molecular Diversity Preservation International
%M DKFZ-2022-00988
%P 5174
%D 2022
%X Somatic loss of function mutations in cohesin genes are frequently associated with various cancer types, while cohesin disruption in the germline causes cohesinopathies such as Cornelia-de-Lange syndrome (CdLS). Here, we present the discovery of a recurrent heterozygous RAD21 germline aberration at amino acid position 298 (p.P298S/A) identified in three children with lymphoblastic leukemia or lymphoma in a total dataset of 482 pediatric cancer patients. While RAD21 p.P298S/A did not disrupt the formation of the cohesin complex, it altered RAD21 gene expression, DNA damage response and primary patient fibroblasts showed increased G2/M arrest after irradiation and Mitomycin-C treatment. Subsequent single-cell RNA-sequencing analysis of healthy human bone marrow confirmed the upregulation of distinct cohesin gene patterns during hematopoiesis, highlighting the importance of RAD21 expression within proliferating B- and T-cells. Our clinical and functional data therefore suggest that RAD21 germline variants can predispose to childhood lymphoblastic leukemia or lymphoma without displaying a CdLS phenotype.
%K RAD21 (Other)
%K acute lymphoblastic leukemia (Other)
%K cohesin complex (Other)
%K germline cancer predisposition (Other)
%K trio sequencing (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:35563565
%R 10.3390/ijms23095174
%U https://inrepo02.dkfz.de/record/179939